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C-di-GMP signaling in Streptomyces

Streptomyces are Gram-positive, filamentous soil bacteria with great industrial relevance, as they produce clinically important antibiotics and other bioactive molecules for medical, veterinary and agricultural use. Their ability to synthesize diverse natural products is temporally and genetically coordinated with a complex developmental life cycle. They grow as a vegetative mycelium of branching hyphae and disperse via spores formed on specialized reproductive structures called aerial hyphae. A major challenge in Streptomyces developmental biology is to dissect regulatory pathways governing differentiation processes in Streptomyces and to understand how environmental stimuli are integrated into these regulatory cascades.

Recently we uncovered that the intracellular levels of the signaling molecule cyclic di-GMP, which is metabolized by GGDEF-type diguanylate cyclases and EAL/HD-GYP-type phosphodiesterases, have a pronounced effect on timing of the developmental programme completion in S. venezuelae. Increased c-di-GMP concentration delays morphological differentiation, whereas low levels of the second messenger favour spore formation in S.venezuelae. Thereby, a tetrameric form of c-di-GMP binds to the developmental master regulator BldD, which results in transcription factor dimerization and consequently repression of sporulation genes. Our current studies aim at identification and characterization of the c-di-GMP signaling components and their mechanisms of action in S. venezuelae developmental biology.

Questions currently addressed include the following:

  • Which diguanylate cyclases and phosphodiesterases have an impact on differentiation processes in S. venezuelae?
  • Which of the GGDEF-, EAL- and HD-GYP-proteins are enzymatically active and how are they expressed and regulated in space and time?
  • Which diguanylate cyclases and phosphodiesterases are responsible for synthesis and degradation of c-di-GMP sensed by BldD? Is direct protein-protein interaction and thus local signaling involved in BldD-containing second messenger control module?
  • Do other c-di-GMP effector proteins exist in S. venezuelae? What is the physiological role of these potential other effectors?

Tschowri N, Schumacher MA, Schlimpert S, Chinnam NB, Findlay KC, Brennan RG, and Buttner MJ. (2014) Tetrameric c-di-GMP mediates effective transcription factor dimerization to control Streptomyces development. Cell 158: 1136-1147

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